The present invention relates to formulations for lipid vesicles and methods of their manufacture. More particularly, the present invention discloses paucimellar lipid vesicles designed of materials which have exceptional properties for cosmetic, edible, dermatological, and pharmaceutical use. The paucimellar vesicles have 2-10 lipid bilayers surrounding a large, amorphous central cavity which contains a water-immiscible oily material including triglycerides supplied by avocado oil unsaponifiables. The lipid bilayers of these vesicles contain at least one non-phospholipid amphiphile as the primary structural material of the lipid bilayers, along with phytosterol from avocado oil unsaponifiables which acts as a membrane or bilayer modulator.
Lipid vesicles are substantially spherical structures made of amphiphiles, e.g., surfactants or phospholipids. The lipids of these spherical vesicles are generally organized in the form of lipid bilayers, e.g., multiple onion-like shells of lipid bilayers which encompass an aqueous volume between the bilayers. Paucilamellar lipid vesicles have 2-10 peripheral bilayers which surround a large, unstructured central cavity.
Until recently, liposome technology has been concerned mostly with vesicles composed of phospholipids. This is primarily because phospholipids are the principal structural components of natural membranes and, accordingly, lipid vesicles have been used as a model system for studying natural membranes. However, there are a number of problems associated with using phospholipids as synthetic membranes. Biological membranes are stabilized by membrane proteins and maintained by extensive enzymatic "support" systems that rapidly turn over, exchange or modify membrane lipids. Neither membrane proteins nor the requisite enzymatic support systems can be practically incorporated into the wall structure of liposomes, making the structures inherently less stable than natural membranes. In addition, the biological environment contains several potent phospholipases that rapidly break down free phospholipids. These phospholipids will attack liposomes and degrade the membrane. For these reasons, phospholipid liposomes placed in an in vivo environment are rapidly degraded.
Moreover, phospholipid liposome technology has other problems. Phospholipids are labile and expensive to purify or synthesize. In addition, classic phospholipid liposomes are in the form of multilamellar as opposed to paucilamellar vesicles and have poor carrying capacities, especially for lipophilic materials, and have poor shelf lives unless lyophilized in the dark with antioxidants. While unilamellar vesicles (these only having one bilayer) add additional carrying capacity, they are much less stable. Finally, phospholipids degrade too rapidly in vivo for most pharmaceutical or vaccine applications.
For these reasons, there is increasing interest in liposomes made of commercially available nonphospholipid amphiphiles (see, e.g., U.S. Pat. No. 4,217,344, U.S. Pat. No. 4,917,951, and U.S. Pat. No. 4,911,928). These molecules have a hydrophilic "head" group attached to a hydrophobic "tail" and are derived from long chain fatty acids, long chain alcohols and their derivatives, long chain amines, and polyol sphingo- and glycerolipids. Commercially available amphiphile surfactants include, for example, the BRIJ family of polyoxyethylene fatty ethers, the SPAN sorbitan fatty acid esters, the TWEEN ethoxylated sorbitan fatty acid esters, glyceryl monostearate, glyceryl distearate, and glyceryl dilaurate, all available from ICI Americas, Inc. of Wilmington, Del.
Paucilamellar vesicles comprised of such non-phospholipid amphiphiles provide a number of advantages over classical phospholipid multilamellar liposomes. For instance, these vesicles have a high carrying capacity for water-soluble and water immiscible substances. Also, the amphiphiles used to make up the vesicle bilayers can often be used as emulsifiers or thickeners, providing the "feel" to certain cosmetics and/or dermatologicals. Furthermore, many of these amphiphiles fall under the GRAS list of edible materials and therefore can be used in many food and pharmaceutical products.
It has previously been shown that when forming lipid vesicles containing at least one amphiphile as the primary lipid of the bilayers, the addition of a membrane modulator considerably improves the shape and size of lipid vesicles, as well as the consistency of the formulation after processing (See e.g., U.S. Pat. No. 5,260,065). In the past, cholesterol has generally been used for this purpose. Sterols such as cholesterol also act to modify the thermotropic phase transition of the amphiphiles. However, cholesterol has the drawback of being an undesirable ingredient for use in most edible and pharmaceutical preparations.
Avocado oil unsaponifiables (a source of phytosterol) can be used instead of cholesterol as a bilayer modulator and provides many cosmetic, dermatological and pharmaceutical benefits. For example, it has a soft waxy consistency that confers a creamy texture to skin care products in addition to its moisturizing effects. Avocado oil unsaponifiables are also non-cytoxic, non-irritating and edible.
Accordingly, an object of the present invention is to provide a method of making paucimellar lipid vesicles using materials which are edible and/or have cosmetic, dermatological and pharmaceutical benefits.
Another object of the invention is to provide paucilamellar lipid vesicles which contain a blend of at least one non-phospholipid amphiphile as the primary structural material of the bilayers and phytosterol supplied by avocado oil unsaponifiables as a modulator.
A further object of the invention is to provide a method of producing paucimellar lipid vesicles which readily encapsulate water immiscible oily materials and are manufactured from relatively inexpensive materials.
These and other objects and features of the invention will be apparent from the following description and the claims.